The ability to increase minute ventilation (VE=respiratory rate times tidal volume) in response to hypoxia is essential for survival. Failure to breathe more often when oxygen levels are low can contribute to respiratory distress in newborn mammals and to sleep apnea in adults. The mechanisms by which hypoxic stimuli are processed are poorly understood. However, it is known that VE increases linearly with decreasing oxyhaemoglobin saturation (about 0.6 l/min percent saturation in healthy individuals) and that its regulation involves input to brainstem areas such as the NTS, that are rich in nitric oxide synthase (NOS). This increase in breathing is regulated not only by the mere lack of oxygen, but rather by molecules related to a different gas, nitric oxide (NO), which affect respiratory centers at the base of the brain. These respiratory centers include neurons present in the brain stem as well as those in the carotid body.
Abnormalities of central control of ventilation, particularly in response to hypoxia, can be life-threatening. Central apnea and hypoventilation occur in patients with congenital and acquired brain stem abnormalities, ranging from Arnold Chiari malformation to scar tissue associated with treatment of brainstem tumors. Furthermore, an apneic or hypoventilatory response to hypoxemia can occur in patients with obstructive sleep apnea, and abnormal dependence on hypoxic ventilatory drive can also make oxygen therapy life-threatening in patients with chronic obstructive lung diseases. A newborn infant (particularly the premature and/or anemic infant) can have a paradoxical apneic or hypoventilatory response to hypoxemia that is believed to play a role in the pathogenesis of some cases of Sudden Infant Death Syndrome. Other patients may have profound paradoxical hypoventilation when asleep, as seen in congenital central hypoventilation syndrome.
Current therapeutic options for each of these disorders are limited primarily to techniques involving artificial ventilation. Of note, therapeutic options for respiratory alkalosis associated with acute hyperventilation (whether psychiatric or drug-induced) are similarly limited. The present invention is directed to a novel approach to the treatment of disorders of control of breathing that is based on the use of nitrosylating agents to enhance minute ventilation in such individuals.